Nitric oxide in breast cancer: Induction of vascular endothelial growth factor-C and correlation with metastasis and poor prognosis
Nitric oxide in breast cancer: Induction of vascular endothelial growth factor-C and correlation with metastasis and poor prognosis
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DOI：
10.1158/1078-0432.ccr-05-1269
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发表时间：
2006-02-15
影响因子：
11.5
通讯作者：
Kakudo, K
中科院分区：
文献类型：
--
作者：
Nakamura, Y;Yasuoka, H;Kakudo, K
目的：通过淋巴管转移到区域淋巴结是癌症进展中的常见步骤。最近的证据表明，血管内皮生长因子-C（VEGF-C）的肿瘤生产促进淋巴管生成，这反过来又促进淋巴转移。实验设计：在诱导和/或抑制NO合成后，在MDA-MB-231乳腺癌细胞中评估亚硝酸盐/硝酸盐水平和VEGF-C产生。在原发性人乳腺癌中分析了硝基酪氨酸的形成，硝基酪氨酸是体内NO形成过氧硝酸盐的生物标志物，并进行了长期随访。nitrotyrosine水平和淋巴结状态，VEGF-C免疫反应性，和其他已建立的临床病理变量，以及预后之间的关系进行了analysed.Results：生产的亚硝酸盐/硝酸盐和VEGF-C在MDA-MB-231细胞增加治疗与NO供体DETA NONOate。NO合成酶抑制剂N-G-硝基-L-精氨酸甲酯消除了这种增加。在57.5%（65/113）的浸润性乳腺癌中观察到高度硝基酪氨酸染色。硝基酪氨酸水平与VEGF-C免疫反应性和淋巴结转移显著相关。通过Kaplan-Meier方法确定的生存曲线显示，高硝基酪氨酸水平与无病生存期和总生存期降低相关。在多变量分析中，高硝基酪氨酸水平出现作为一个显着的独立预测因子的总survival.Conclusions：我们的数据显示了一个作用，NO在刺激血管内皮生长因子-C的表达在体外。其生物标志物硝基酪氨酸的形成也与VEGF-C表达和淋巴结转移相关。此外，高硝基酪氨酸水平可能是乳腺癌长期生存的重要预后因素。
Purpose: Metastasis to regional lymph nodes through the lymphatic vessels is a common step in the progression of cancer. Recent evidence suggests that tumor production of vascular endothelial growth factor-C (VEGF-C) promotes lymphagiogenesis, which in turn promotes lymphatic metastasis. Nitric oxide (NO) may also increase metastatic ability in human cancers.Experimental Design: Nitrite/nitrate levels and VEGF-C production were assessed in MDA-MB-231 breast cancer cells after induction and/or inhibition of NO synthesis. Formation of nitrotyrosine, a biomarker for peroxynitrate formation from NO in vivo, was analyzed in primary human breast carcinoma with long-term follow-up. The relationship between nitrotyrosine levels and lymph node status, VEGF-C immunoreactivity, and other established clinicopathologic variables, as well as prognosis, was analyzed.Results: Production of nitrite/nitrate and VEGF-C in MDA-MB-231 cells was increased by treatment with the NO donor DETA NONOate. The NO synthase inhibitor N-G-nitro-L-arginine methyl ester eliminated this increase. High-grade nitrotyrosine staining was observed in 57.5% (65 of 113) of the invasive breast carcinomas. Nitrotyrosine levels were significantly correlated with VEGF-C immunoreactivity and lymph node metastasis. Survival curves determined by the Kaplan-Meier method showed that high nitrotyrosine levels were associated with reduced disease-free and overall survival. In multivariate analysis, high nitrotyrosine levels emerged as a significant independent predictor for overall survival.Conclusions: Our data showed a role for NO in stimulating VEGF-C expression in vitro. Formation of its biomarker nitrotyrosine was also correlated with VEGF-C expression and lymph node metastasis. Furthermore, high nitrotyrosine levels may serve as a significant prognostic factor for long-term survival in breast cancer.